Influenza vaccination strategies have been relatively constant for at least about 20 years. Typically, each vaccine comprises inactivated flu virus particles from approximately three different strains. These vaccines are given in order to induce antibody based responses. Each year, the World Health Organisation (WHO) selects the strains which it considers to pose the greatest threat to human health at that time. Two decisions per year are typically issued, one for Northern hemisphere strains and one for Southern hemisphere strains. Following the announcement, manufacturers then have a short period of time in order to make that year's vaccine formulations. This strategy leads to a number of problems. Firstly, due to the short manufacturing window, complications in production can arise. Delays can occur in the system, for example when particular strains are unavailable or when substitutions need to be made. Moreover, higher level problems are presented by this strategy. For example, this strategy effectively represents a statistical gamble on the particular serotypes of influenza which might pose the greatest threat to human health. However, the various populations of flu viruses change dynamically with time. Therefore, the lag between choice of strains and vaccination following manufacture can mean that the vaccine formulations may no longer represent the optimal formulations even at the time of administration. In addition, shortages of the vaccine are very common. The reason is that manufacturers are unable to sell excess aliquots of vaccine since the vaccine formulation is updated each year and there is no market for the previous year's composition. This reason alone means that the whole population cannot be vaccinated. Vaccinations tend to be focussed on perceived risk groups. One such risk group is the elderly. However, this strategy itself may be flawed since studies comparing the effects of vaccinating the elderly subjects at risk with the effects of vaccinating the same subjects together with each individual with whom they have contact demonstrate that in order to be effective, those individuals with whom the at risk patients come into contact need to be vaccinated in order for the strategy to be effective.
In addition to the above, the biology of influenza viruses means that the external proteins of the virus change over time. This is part of the natural host defence evasion behaviour of the virus. Furthermore, new serotypes come into humans from other species, such as from avian species, for example by re-assortment or other genetic mechanisms. This again leads to serotypes with different external proteins. Clearly, with the external proteins of the virus continually changing, the hopes of a conventional vaccine design remaining effective from year to year are remote. Current vaccines for influenza A act by stimulating production of antibodies to haemagglutinin (HA) and neuraminidase (NA). As these proteins are highly polymorphic, there is very little or no cross-subtype (or heterosubtypic) protection and limited cross-strain protection even within subtypes. As noted above, there is a need for constant redesign and remanufacture which increases the cost of the vaccines, places limitations on supply, and most importantly means that vaccines for newly arising strains can only be produced once the HA and NA sequences of viruses posing the greatest threat to human health have been identified. Avian influenza in humans is currently treated with the anti-viral drug oseltamivir, and this drug is now being stockpiled for use in future pandemics. However, oseltamivir resistant H5N1 virus has now been isolated following human infection, so the use of this drug alone may not be sufficient to treat infected individuals or limit the spread of the virus should it become transmissible from human to human. From the 59 known human cases of H5N1 influenza it is striking that the majority of infections have been found in young people, and that the case fatality rate among those less than 15 years of age was 89%.
Natural infection with influenza virus results in T cell responses to NP and M1, but subunit vaccines consisting of HA and NA cannot induce these responses. A cold-adapted (ca), live-attenuated virus vaccine for intranasal immunisation has now been licensed in Russia and the USA. Vaccines produced in this way have been shown to induce some cross-protective immunity. Trials were carried out in seronegative children vaccinated with a ca virus. The level of seroconversion to the vaccine strain ranged from 41 to 89%, with the level of seroconversion to different strains ranging from 5 to 55%. The cross-reactivity is therefore low, and as with subunit vaccines, a new mix of virus strains is used to produce a vaccine for each year. Further, safety concerns related to vaccine strain shedding have resulted in this vaccine being approved only for the age-group 5-49 in the USA. This excludes two major risk groups who are older or younger than the defined age range, as well as immunodeficient patients and pregnant women. The risk of a major global pandemic of avian influenza has created widespread and justified concern. Vaccination presents a potential control measure but there is no vaccine licensed against H5N1 influenza and recent trials of new investigational H5N1 vaccines suggested that a 12 fold greater amount of antigen would be need per vaccine course than with other flu vaccines. This has discouraged further development of vaccines due to the manufacturing parties being concerned that if a pandemic does not occur they will be left with unsold supplies. Other attempts to solve these problems have focussed on the use of adjuvants to reduce the amount of antigen needed. Moreover, the current high rate of diversification of H5N1 strains suggests that vaccines made now may differ so much in their H5 sequence from any pandemic strain that emerges that these vaccines would have little or no efficacy.
Mice immunised with DNA vaccines expressing nucleoprotein (NP) and matrix (M1) from H1N1 virus have been shown to be protected against lethal challenge with an H5N1 strain (Kreijtz et al 2007 Journal of Infectious Diseases vole 195 p. 1598). Using a DNA prime/adenovirus boost regime with vaccines expressing NP, T cell dependent protection against numerous influenza A subtypes including H5N1 has been demonstrated in mice. However, in humans DNA vaccines are not good immunogens and do not boost pre-existing responses. Recombinant MVA expressing HA or NP from equine influenza administered with or without a DNA vaccine prime has recently been shown to induce antibodies, lymphoproliferation and interferon gamma production in ponies (Breathnach et al 2004 Veterinary Immunology and Immunopathology vol 98 pp 127-136) However, two booster doses of MVA were used, no challenge studies are disclosed and no efficacy was demonstrated.
The invention seeks to overcome problem(s) associated with the prior art.